The mainstay of modern medicine is drug therapy, which employs drugs for treating or preventing various diseases. Almost all drugs employed in drug therapy (e.g., low-molecular-weight compounds) intrinsically are foreign substances to the human body, and thus administration of such drugs provides therapeutic efficacy, but may cause a variety of side effects. Such side effects often compel the drug therapy to be abandoned. Also, some drugs have encountered a situation where research and development have to be suspended due to severe side effects, although the drugs have been proved to be useful for patients with a certain disease. Moreover, the use of some other drugs is strictly regulated in order to detect the sign of their side effects by mandatory examinations.
According to the statistics published in the United States, the cases of drug-induced side effects account for two millions or more a year, and more than 100 thousand due to such side effects (JAMA, 279, 1200 (1998)). In Japan, 26,545 cases of drug-induced side effects (including redundantly reported cases) were reported, and 1,239 deaths due to such side effects only in one year of 2000 (Ministry of Health, Labor and Welfare, Jun. 6, 2003, House of Representatives, Responsive Pleading No. 55).
Among side effects due to drug administration, granulocytopenia is a fatal side effect. Particularly, a decrease in granulocytes tends to lead to an infection, and onset of agranulocytosis involves a very high risk for a serious infectious disease such as pneumonia or sepsis. Examples of drugs that are generally known to induce granulocytopenia include analgesic-antipyretic drugs (aminopyrine), antibiotics (Chloromycetin), antithyroid drugs (Mercazole), anticonvulsant drugs, antidiabetic drugs, and diuretic drugs. Occurrence of side effects caused by such a drug is less likely to be related to its dose, and is considered to be related to the predisposition of a patient (e.g., allergic predisposition or idiosyncrasy). Therefore, occurrence of such side effects is almost impossible to predict. In order to avoid occurrence of such side effects, doctors must handle respective cases very carefully, through detailed interviews with individual patients regarding, for example, drug administration records in other departments, and analysis of blood test results, etc. Notably, if and when a patient has onset a side effect of granulocytopenia, doctors must take immediate measures, including hospitalization.
Other drugs that are known to induce granulocytopenia include dibenzodiazepine (clozapine), which is an antipsychotic drug. This drug is expected to have high efficacy, but clinical trials of the drug have been suspended in Japan.
Other drugs that induce granulocytopenia include vesnarinone, which has inhibitory activities on PDE3 and K channel. This drug is an effective inotropic drug that is less likely to cause arrhythmia and other cardiac events (e.g., onset of heart failure and hospitalization). However, administration of this drug may cause side effects; i.e., leukopenia, granulocytopenia, and subsequent agranulocytosis. Therefore, the use of this drug is strictly limited.
Single nucleotide polymorphisms (SNPs) are the most frequently used genetic markers in human genetic analysis. SNPs have already been shown to be useful markers for an association study between genetic background and common diseases or drug response (see Non-Patent Documents 1, 2, and 3). As has been known, analysis of haplotype, constructed of multiple SNPs, is useful for analysis of the susceptibility of polygenic diseases (see Non-Patent Documents 4 and 5). In practice, some diseases such as Alzheimer's disease and hypertension have already been intensively analyzed by such an analysis method (Jeunemaitre, X., et al., Am. J. Hum. Genet., 60, 1448-1460 (1997); Martin, E. R., Am. J. Hum. Genet., 67, 383-394 (2000)).
In recent years, advances in genome analysis have led to development of toxicogenomics, which studies relationship between genes and toxicities such as the effect of a drug on cytochrome P450 (CYP) (i.e., a drug-metabolizing enzyme) Particularly, association studies of individual genetic background and sensitivity/response has been proposed as a powerful tool to elucidate the cause of adverse effects. So-called tailor-made therapy is expected to be realized through these approaches
Non-Patent Document 1: Brookes, A. J., “The essence of SNPs,” Gene, USA, (1999), 234, 177-186
Non-Patent Document 2: Cargill, M, et al., “Characterization of single-nucleotide polymorphisms in coding regions of human genes,” Nature Genet., USA, (1999), 22, 231-238
Non-Patent Document 3: Evans, W. E., & Relling, M. V., “Pharmacogenomics: translating functional genomics into rational therapeutics,” Science, USA, (1999), 286, 487-491
Non-Patent Document 4: Stephens, J. C., et al., “Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes,”Am. J. Hum. Genet., USA, (1998), 62, 1507-1515
Non-Patent Document 5: Tishkoff, S. A., et al., “The accuracy of statistical methods for estimation of haplotype frequencies: an example from the CD4 locus,” Am. J. Hum. Genet., USA, (2000), 67,